The rationale driving this project is that there are natural cells in the body that are known to express peripheral tissue antigens (pTAs) and induce tolerance to self-reactive lymphocytes in vivo. We have discovered that MSCs also express these pTAs and can maintain this expression during ex vivo processing unlike other pTA expressing cells. We hypothesize that the expression of self antigens by MSCs is essential for the therapeutic efficacy of cell transplants in models of autoimmune disease, and therefore may be amenable to ex vivo monitoring/optimization to create a tailored cell therapy. The objectives are to evaluate the relevance of pTA expression in the immune response to MSCs, both in vitro and in vivo, and image these cell grafts during the treatment of an antigen-specific model of intestinal autoimmunity. The long-term goal is to evaluate this use of a unique form of antigen presentation by MSCs as a therapeutic mode of action and essentially create a new drug class based on antigen-specific stem cell grafts. PUBLIC HEALTH RELEVANCE: This is a Mentored Research Scientist Development Award application for Dr. Biju Parekkadan a biomedical engineer by training with specialization in cell-based therapy. He has developed new treatment approaches that harness the natural functions of mesenchymal stem cells (MSCs) for therapy. Recently, he has discovered a new function of MSCs that has significant relevance to the fields of autoimmunity and transplantation. As a recently appointed postdoctoral fellow, Dr. Parekkadan submits this five-year career development plan under the mentorship of Drs. Martin L. Yarmush, the Helen Andrus Benedict Professor of Surgery and Bioengineering at Harvard Medical School and the director of the Center for Engineering in Medicine, Ralph Weissleder, Professor of Radiology at Harvard Medical School and the director of the Center for Molecular Imaging Research at the Massachusetts General Hospital and Diane Mathis, Professor of Immunology and Immunogenetics at Harvard Medical School. The award includes extensive: (1) hand-on training in radiological and immunological studies of cell transplants in vivo, (2) academic courses and seminars, and (3) guidance of a selected advisory committee towards the future large-scale research projects.